Early glycaemic changes after initiation of oral antidiabetic medication and risk of major adverse cardiovascular events: results from a large primary care population of patients with type 2 diabetes

Aims To determine the risk of major adverse cardiovascular events (MACE) and death, associated with an early large and rapid decline in glycated haemoglobin (HbA(1C)) following first time initiation of an oral antidiabetic drug (OAD). Methods and results We included 10 518 primary care patients with type 2 diabetes, who initiated an OAD for the first time. For each individual, we measured a decline in HbA(1C), as the difference between the pre-treatment HbA(1C) (within 3months before OAD initiation) and the post-treatment HbA(1C) (within 1.5-4.5months after OAD initiation), divided by the time between the two measurements. The decline was reported in mmol/mol change per 3months in HbA(1C) and categorized by the median decline into levels of steep [>= 9mmol/mol (>= 0.8%)] and flat decline [<9mmol/mol per 3months (<0.8%)]. Pre-treatment HbA(1C) was categorized by the median, into levels of low (48-62mmol/mol) and high (>62mmol/mol). Multiple Cox regression was used to study the effect of decline (steep vs. flat) on the outcome hazard rates separately for patients with low and high pre-treatment HbA(1C). Analyses were adjusted for age, sex, traditional cardiovascular risk factors, severe comorbidities, and concomitant medication treatment. During a median follow-up time of 7.7years, 1625 developed MACE and 2323 died. We found that a steep decline vs. a flat decline was significantly associated with a decreased hazard for MACE, both in individuals with high [hazard ratio (HR) 0.81; 95% confidence interval (CI) 0.69-0.94; P=0.005] and low pre-treatment HbA(1C) (HR 0.79; 95% CI 0.66-0.96; P=0.015). The hazard of MACE was more pronounced on the short-term vs. long-term in individuals with high pre-treatment HbA(1C). We found no significant association between combinations of pre-treatment HbA(1C) and decline categories and hazard of all-cause mortality. However, a combination of a low pre-treatment HbA(1C) and steep decline was associated with increased 1-year mortality (HR 1.52; 95% CI 1.00-2.29; P=0.048) and hypoglycaemia (HR 1.82; 95% CI 1.11-2.98; P=0.017). Conclusion A combination of a high pre-treatment HbA(1C) and a steep decline in HbA(1C) was associated with a decreased short-term risk of MACE. A low pre-treatment HbA(1C) and a steep decline was associated with a long-term reduced risk of MACE, but a short-term increased risk of death and hypoglycaemia.